A. Introduction

It is known that an average human consumes 550 liters of oxygen daily, which is 19 cubic feet/day or 631 lbs a year. The starting point for this process is the inhalation of air, which is 20% oxygen and 80% nitro gen, and the exhaled air is reduced to 15% oxygen. The explanation for the reduction from 20% to 15% is because 5% of the inhaled oxygen has been absorbed by the hemoglobin present in the erythrocyte cells of the blood as they pass through the lung. After leaving the lung, the red blood cells travel throughout the total circulatory system of the body so that it can off-load the oxygen bound to the hemoglobin. The released O2 can then diffuse to all the cells throughout the body where it is utilized by metabolic processes. This analysis explains the basis for the statement that an adult human uses ~550 liters or 19 cubic feet of oxygen per day. The key to understanding in detail this information is to appreciate the properties of the protein hemoglobin and the related process of hematopoiesis.

The various cellular components of blood are produced by the hematopoietic system. The main components of the hematopoietic system are the bone marrow and all the blood present in the circulatory system. In addition, the liver and spleen are key accessory organs. The spleen, which is located in the left upper quarter of the abdomen, is ~1″ × 3″ × 5″ in size. The spleen is important for many functions in the body, from degrading and filtering out old retired red blood cells to creating antibodies. But surprisingly, the spleen is not essential for life. The spleen also stores platelets that normally help in blood clotting and coagulation. The liver stores vitamin B12 which is essential for erythrocyte pro duction as well as the biosynthesis of hemoglobin.

Erythrocytes are also described as red blood cells. All erythrocytes contain significant amounts of hemoglobin. The main biological property of hemoglobin’s function is to capture and specifically bind the oxygen that has been inhaled by the lungs. The oxygen binds specifically to a heme group present in each hemoglobin molecule (this will be discussed in more detail under the topic erythropoiesis). The major function of the oxygenated hemoglobin is for the erythrocytes to deliver the hemoglobin/O2 through the circulatory system (arteries, capillaries, venules, etc.) to all the body’s cells. In addition, after the hemoglobin has released its bound oxygen, it has the equally important responsibility to carry a significant proportion of the waste car bon dioxide (CO2) from all metabolizing cells back to the lungs for exhalation (excretion from the body).

Bone marrow is the flexible tissue in the interior of bones and it contributes ~4 % of the total body weight. Each erythrocyte is created from a stem cell released in the bone marrow. The term “erythron” describes the total mass of the circulating precursors and the mature red blood cells that are present in the blood compartment. Another way to describe the erythron is as a dispersed organ whose prime function is the trans port of oxygen in the outbound direction (from the lungs) to all the cells of the body and the transport of carbon dioxide in the inbound direction (back to the lungs), and as well, the maintenance of the blood pH. In adults, the erythron is in a steady state where the loss of cells is precisely balanced by the new production of cells. Every minute of every day an adult human must biosynthesize approximately 150 million erythrocytes and 120 million granulocytes, as well as numerous mononuclear cells and platelets; see Table 1. Or stated differently, adult humans’ erythrocytes are produced at a rate of 2–4 million every one second!! There are numerous hormones and regulatory processes that control the crucial aspects of the various cell populations of the erythron.

Table1. Cellular Components of Blood

A detailed consideration of the complexities of the overall hematopoietic process is beyond the scope of this presentation. The focus will be on the process of erythropoiesis, the protein erythropoietin, and the function of red blood cells.

B. Process of Erythropoiesis

The process of producing red blood cells (RBC) is labeled erythropoiesis. In humans the erythropoietic process occurs exclusively in the red bone marrow of all the bones from birth to ~ages 5–20 years. Over the interval of 5 to 20 years, the long bone marrow slowly loses its capability to provide red blood cells. By the age of 20, the responsibility of carrying out erythropoiesis is retained only by the bone marrow of the ribs, sternum, and the pelvis.

The process of producing red blood cells is completely dependent upon the availability of a protein hormone, erythropoietin (EPO), which is secreted by the kidney. When the kidney detects low levels of oxy gen in the blood, it promptly releases the protein erythropoietin, which then arrives shortly at the body’s bone marrow via traveling through the blood circulatory system; see Figure 1A.

Fig1. Role of the kidney in blood erythropoiesis. (A) Illustration of the collaboration between the kidney as a source of the hormone erythropoietin and the skeletal system as a bone marrow site to biosynthesize hemoglobin for the red blood cells. The protein hormone erythropoietin (EPO) is critical for the production of the red blood cells for the whole body. The renal cortex of the kidney is the source of production of EPO. When the kidney senses the lack of oxygen (hypoxia is the condition when oxygen is lower than the normal level) it mobilizes the production and secretion of the glycoprotein hormone, erythopoietin (EPO). EPO is biosynthesized in the peritubular capillary lining cells of the renal cortex region of the kidney. The EPO then moves through the circulatory system and ultimately binds to the EPO receptors associated with proerythroblasts present in the bone marrow of the entire skeleton. This is the site of production of the hemoglobin that is produced for all the red blood cells. (B) Mode of action of erythropoietin in the regulation of gene expression. After the secretion of erythropoietin into the circulatory system, it ultimately is taken up by erythrocytic progenitor myeloid stem cells present in the bone marrow. One erythropoietin hormone molecule binds to two collaborative receptors present in the cell membrane of myeloid stem cells. The receptors activate the JAK2 and STATS pathways of PI3K – Akt/PKB, Ras-MAPK, and the NF-kB pathway. Collectively these pathways stimulate the production of differentiation and growth of the myeloid stem cells into intermediate cell types (basophillic erythroblasts and then more mature erythroblasts that have lost their nucleus). (C) Summary of the process of erythropoiesis which throughout life is producing new erythrocytes necessary to transport oxygen to all cells in the body. The starting point is activation of the myeloid stem cell, followed by differentiation into proerythroblasts, basophillic erythroblasts, with their cell nucleus and then without their cell nucleus, followed by differentiation into the final reticulocyte, which can join the large family of erythrocytes.

EPO is biosynthesized in the peritubular capillary lining cells of the renal cortex region of the kidney. The EPO then moves through the circulatory system and ultimately binds to the EPO receptors associated with proerythroblasts present in the bone marrow of the entire skeleton; see Figure 1, panels A/B/C. This is the site of production of the hemoglobin that is produced for all the red blood cells.

C. Erythropoietin (the Protein)

 Erythropoietin is the hematopoietic hormone secreted by the kidney that functions as a major stimulator for the production of erythrocytes. Erythropoietin is a secreted glycoprotein of 165 amino acids, but with a mature molecular mass of 30–34 kDa due to the presence of a significant amount of covalently linked carbohydrate. Hypoxia (a low-oxygen environment) can stimulate the synthesis of erythropoietin mRNA in the renal capillary tubular cells by unknown mechanism(s). In the adult human, erythropoietin is a classic hormone, secreted by the kidney and transported systemically to its site of action in the erythron.

Each molecule of hemoglobin is composed of two paired amino acid chains of α2β2 with a molecular weight of ~16,000. The four heme prosthetic group is synthesized in the cytosol and mitchondria of the immature red blood cells; see the proerythroblasts, basophillic erythroblasts, and erythroblasts in Figure 1, panel C. Each heme group binds one O2 and the intact hemoglobin molecule α2β2 normally carries four oxygen O2 molecules linked to four separate heme groups. The intact human erythrocytes survive only ~120 days, which justifies the necessity for a vigorous production of erythrocytes in the bone marrow.

The important biological property of EPO is that it is anti-apoptotic. See Figure 1B. Thus, when EPO binds to the erythopoietin receptor as a homodimer in the plasma membrane, it results in the activation of the cytoplasmic Janus-2 kinases (JAK2) pathway which catalyzes the phosphorylation of tyrosine residues of the EPO-receptor as well as of intracellular proteins (transcription factors and enzymes). Collectively these actions facilitate the production and maturation of the reticulocytes in the bone marrow compartment which supports the essential differentiation and growth properties of the myeloid stem cells.

Figure 1C illustrates a summary of the process of erythropoiesis which throughout life is producing new erythrocytes necessary to transport oxygen to all cells in the body. This is dependent upon converting the myeloid stem cell successfully into proerythroblasts, then basophillic erythroblasts, erythroblasts (with and then without a nucleus), and finally into reticulocytes. They are then released/secreted and circulate in the body’s blood compartment for ~1 day while they complete development into mature erthrocyte red blood cells.

The red blood cells are functionally active for ~3–4 months and then they begin to deteriorate. This is because the red blood cell’s membranes have become fragile as a result of many passages through narrow arterioles and capillaries, which can physically disrupt and break the red blood cell. These damaged red blood cells are eventually taken out of the general circulation when they pass through the spleen, which breaks them down further. Also the iron is released from the hemoglobin group and is recycled to be incorporated into a new red blood cell.

D. Hemoglobin

Both H+ and O2 bind directly to hemoglobin with an inverse affinity that is pH dependent. In the presence of high oxygen, hemoglobin binds oxygen and releases protons. But when oxygen concentration is low, hemoglobin binds H+ and oxygen is released. As will be discussed below, hemoglobin binds O2 specifically to iron Fe2+ in a heme group. The proton, H+, binds randomly to several of hemoglobin’s amino acids, such as histidine.

Hemoglobin binds oxygen cooperatively and generates two conformations designated as the R state (relaxed) and T state (taut). Oxygen has a much higher affinity for hemoglobin in the R state. When the oxygen concentration is reduced or absent, the T state of hemoglobin is dominant. Some of the consequences of changes in pH are illustrated in panel C of Figure 2.

Fig2. Hemoglobin as a carrier of oxygen in the circulatory system. (A) X-ray crystallographic structure of hemoglobin. Hemoglobin has a molecular weight of 64,500. It is comprised of three components: (i) two α chains (each 146 amino acids), each folded as a red α helix; (ii) two β chains (each 141 amino acids), each folded as a blue α helix; and (iii) four heme prosthetic groups that are separately associated with one of the four α-helices. Each molecule of hemoglobin can bind four molecules of oxygen (O2) with one O2 per heme group. (B) Structure of hemoglobins heme group with bound oxygen. Each of the four heme groups, known as protoporphyrin IX, has a bound iron atom in its ferrous oxidation state (Fe2+). The four protoporphyrin IXs each has four planar pyrrole rings that are connected together by methylene bridges. Each of the four pyrrole rings is colored peach. (C1) The pH dependency of oxygen binding to hemoglobin. This figure reports the difference in fractional occupancy of the oxygen binding sites on the heme groups of hemoglobin as a function of the pH of the local environment. The comparison was made between a pH 7.6 (less acidic) environment (green line) with that of a lower pH 7.2 (more acidic) environment (red line). At the lower 7.2 pH, the fractional binding of 50% was achieved at a pressure of 4.2 kPa. In contrast, at the higher pH of 7.6, a reduction of the pressure to 2.6 was still adequate to achieve a 50% occupancy of the hemoglobin binding sites. Or to analyze the data differently, at an oxygen pressure of 4.2 kPa, for a pH 7.2, only a 50% occupancy was achieved, while for the pH of 7.6 a higher occupancy of ~75% was achieved. (C2) Physiological effects of oxygen binding to hemoglobin. This panel shows two oxygen-binding curves to hemoglobin, one for a normal healthy individual (dark green line) and one for a person with sickle cell anemia (red line). Sickle cell anemia is a genetic disorder and the anemia can be passed through family generations. The red blood cells which are normally shaped like a disc take on a bold sickling or crescent shape, which makes it difficult for the red blood cells to move through large arteries in the lung and small capillaries in many locations of the body. The specific cause is a mutation in the hemoglobin gene. The classic circular shape of the erythrocytes becomes grossly altered to an abnormal rigid sickle shape (see Figure 1, panel C). Thus, as shown here, the hemoglobin from an anemic individual is only able to bind ~50% of the oxygen (red line) as compared with the ~100% for a normal individual (green line).

When the hemoglobin that is present in the circulatory system passes through the lungs (in the presence of high concentrations of oxygen in the blood from inhalation), the pH is ~7.6, and it is relatively easy to saturate the hemoglobin with O2. See Figure 2, panel C. In contrast, when the blood hemoglobin is passing in the peripheral tissues, the pH is on the low side (~ pH 7.2, or more acidic) and the extracellular O2 concentration is intrinsically much lower (due to the metabolic use of O2 in intermediary metabolism of all the tissues). Thus the newly O2 saturated hemoglobin arriving in the peripheral tissues from the lungs is readily able to dissociate O2 from the heme state (Fe2+). This then allows the hemoglobin to convert to the Relaxed state where it is optimized to carry two end products of cellular respiration, namely CO2 and H+, from the tissues back to the lungs and kidneys where they are excreted.

Another useful consequence of hemoglobin’s T state in the peripheral tissues is that ~35% of the total H+ and ~20% of the total CO2 that is released as a waste product of intermediary metabolism can bind to hemoglobin and be transported back to the lungs, where they are exhaled, and kidneys, where they are excreted. The remainder of the CO2 is dissolved in water along with the H+ which generates bicarbonate (HCO3^-) and moves through the circulatory system back to the lungs, where it is converted back to CO2 and is exhaled.

The heart of the hemoglobin structure is shown in Figure 2, panels A/B. The covalent linkage of four pyrrole rings to one another collectively confers upon the hemoglobin protein the ability to transport oxy gen bound to the Fe2+ in the center of the heme group. The four planar pyrrole rings are each connected, in an “oval,” by methylene bridges. Each of the four pyrrole rings in Figure 2B has a peach color. The stoichiometry is one pyrrole ring per one Fe2+ ion which has six coordination bonds. Four of the bonds are in the plane of the overall pyrrole ring, and the other two bonds are perpendicular (one above to an oxygen and one below to a histidine residue of hemoglobin). The Fe2+ ion has a tight bond to O2 and ensures that the O2 will be safely delivered from the lungs through the arteriole system to the peripheral cells.

The four groups of 4 “circular” pyrrole rings are visible (green color) in each of the hemoglobin’s α2β2 subunits (Figure 2A). Thus, one molecule of α2β2 hemoglobin binds four molecules of O2. Also, unfortunately, each pyrrole ring can also bind one carbon monoxide molecule (CO) to the heme group. Since hemoglobin binds CO with a ~250-fold greater affinity than O2, the CO will supplant the normally present O2. This describes why the circumstances of extensive exposure to CO gas can be lethal due to the blocking of transfer of O2 from the lungs to the peripheral tissues.

See Figure 2, panel C; the right panel shows two oxygen-binding curves to hemoglobin, one for a normal healthy individual (dark green line) and one for a person with sickle cell anemia (red line). Sickle cell anemia is a genetic disorder and the anemia can be passed through family generations. The red blood cells which are normally shaped like a disc take on a bold sickling or rigid crescent shape, which makes it difficult for the red blood cells to move through large arteries in the lung and small capillaries in many locations of the body. The specific cause is a mutation in the hemoglobin gene. Thus as shown in Figure 2C on the right side, the hemoglobin from an anemic individual is only able to bind ~50% of the required oxygen (red line) as compared with the ~100% for a normal individual.

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